Purification of dehydroabietylamine



PURIFICATION OF DEHYDROABIETYLAMINE I Richard B. Hasbrouck, Waukegan,Ill., assignor to Abbott fiaboratories, North Chicago, 111., acorporation of linois No Drawing. Application March 10, 1955, Serial No.493,549

Claims. (Cl. 260501) This invention relates generally to the preparationof relatively pure dehydroabietylamine and compounds containing adehydroabietylamine group and more particularly to an improved method oftreating a mixture of hydroabietylamines to obtain therefrom relativelypure dehydroabietylamine and compounds containing the saiddehydroabietylamine group.

Dehydroabietylamine is a unique synthetic primary amine having atricyclic ring structure which is obtained as part of a mixture ofamines prepared by the hydrogenation of rosin acid nitriles and has thefollowing formula:

on, omNn,

es ati Dehydroabietylamine is available commercially under the tradename Rosin Amine D which consists of about 60 to 70 percentdehydroabietylamine and about 30 to percent of a mixture of dihydroandtetrahydroabietylamines and isomeric amines. hydroabietylamines differfrom dehydroabietylamine only by two and four hydrogen atomsrespectively, many of the properties of these hydroabietylamines arevery similar. The similarity of these hydroabietylamines makes theirseparation difficult and relatively expensive.

It has been found that dehydroabietylamine is a useful compound in thesynthesis of certain pharmaceutical preparations. Thus, it can beemployed as an intermediate for the preparation ofN,N'-bis-(dehydroabietyl)-ethylenediamine which forms sparinglywater-soluble reaction products with certain therapeutically usefulcompounds, such as penicillin G, as particularly described in pendingpatent application Serial No. 338,886, filed February 25, 1953, onbehalf of the inventors A. W. Weston and A. F. De Rose, and wherein thecompound N,N-bis-dehydroabietylethylenediamine dipenicillin G isspecifically disclosed. When the rosin amine mixture is used for thepreparation of the foregoing intermediate, however, the dihydroandtetrahydroabietylamine constituents form products which are moredifiicultly recoverable than those derived from substantially puredehydroabietylamine. Therefore, for certain purposes the use ofdehydroabietylamine in relatively pure form results in significantlyincreased yields of the desired therapeutic products. It would thereforebe desirable to separate dehydroabietylamine from the otherhydroabietylamine constituents of a commercial rosin amine mixture.

Therefore, it is an object of the present invention to provide animproved and more economical method of ob- Since dihydroand tetra- I Itisa'further object of the present invention to provide an improved andmore economical process of obtaining a lower fatty acid salt of thedehydroabietylamine in rela tively pure form without having admixedtherewith a substantial proportion of a compound having dihydroandtetrahydroabietylamine groups therein.

It is still another object of the present invention to provide animproved and more economical method of obtaining dehydroabietylamine inrelatively pure form withouthaving admixed therewith substantial amountsof dihydroand tetrahydroabietylamine.

It is also an object of this invention to provide an improved method oftreating a hydroabietylamine mixture containing substantial amounts ofdehydroabietylamine, dihydroabietylamine, and tetrahydroabietylamine inorder to separate therefrom the dehydroabietylamine constituent inrelatively pure form without having admixed therewith substantialamounts of the dihydroand tetrahydroabietylamine constituents of thesaid mixture.

Other objects of the invention will be apparent from the detaileddescription and claims to follow.

It has been found that the lower fatty acid salts of dehydroabietylamineare appreciably less soluble in certain organic solvents than are thecorresponding salts of dihydroand tetrahydroabietylamines. Thesedifferences in solubility form the basis of a means of separatingdehydroabietylamine from dihydroand tetrahydroabietylamines. Morespecifically, it has been :found that the addition of approximately onemolar equivalent of a lower fatty acid to a solution of commercial rosinamine in one of a group of selected solvents causes a crystallineproduct to form which consistsmainly of the salt of dehydroabietylamineand the said fatty acid. The corresponding salts of dihydroandtetrahydroabietylamines largely remain in solution. The crystallineproduct can be separated by filtration or by other known means andconsists mainly of the fatty acid salt of dehydroabietylamine, alongwith considerably smaller amounts of the salts of the other amines. Thesalt so obtained can be recrystallized from one or more of the suitablesolvents to obtain a product which contains an even higher proportion ofdehydroabietylamine than that in the crude salt.

The lower fatty acids-which can be employed to form suitable salts foruse in the above separation procedure are those having between one andeight carbon atoms per molecule and include such compounds as formic,acetic,

propionic, butyric, and caproic acids. From the foregoing group ofacids, acetic acid is the preferred one because of its availability andrelatively low cost. Acetic acid also furnishes good yields of thedesired salt in a relatively high state of purity.

The organic solvents which have been found most useful and suitable forseparating and recrystallizing the fatty acid salts of the rosin aminesare the substantially non-polar organic solvents, such as the petroleumhydrocarbon solvents including hexane and heptane, the latter two beingthe lower aliphatic petroleum hydrocarbon solvents availablecommercially as mixtures of isomers under the trade names Skellysolve Band Skellysolve C, respectively, and di-isopropylether.

In general, the procedure for separating dehydroabietii ylaminefrom theother components in a rosin amine mixtaining compounds containing thedehydroabietylamine group in a relatively pure form.

ing of substantially percent purity. The fatty acidcan beadded in oneportion to a warmed solution of the rosin amine, followed by cooling toobtain crystallization. An alternative method, particularly applicablewhen formic or acetic acid is used, comprises the addition of the fattyacid to the rosin amine solution at room temperature over a period offrom one-half to one hour. When formic or acetic acid is added to theamine solution at room temperature, the desired acid addition saltcrystallizes readily and continuously as the said acid is added. Whenone of the higher fatty acids, such as propionic through octanoic acid,is added to the amine solution at room temperature, however, the acid isadvisedly added in one portion, since the latter acid ad dition saltscrystallize relatively slowly from the amine solution. Aftercrystallization is complete, the product is separated and washed withone or more portions of fresh, cold solvent and then dried. If desired,the product can be recrystallized from the same solvent or from anothersuitable solvent mentioned above. The dehydroabietylamine may beregenerated by dissolving the 'salt in warm water and treating withalkali, whereupon the free-base precipitates as an oil which isseparated, washed with water, dried and distilled, or used directly,

as desired. a

In the following specific examples are shown several specificembodiments of the present invention but it should be understood thatthe invention is not to be limited to the specific reactions disclosednor to the precise proportions or conditions set forth in the severalspecific examples, since the examples are given only for the purpose ofillustrating the principle of the present invention.

Example I Glacial acetic acid, 6.0 gm. (0.1 mole), is added in oneportion to a stirred solution of 28.55 gm. (0.1 mole) Rosin Amine D in360 cc. Skellysolve C at 70-75 -C. The solution is allowed to cool withstirring, and at about 60 C. crystallization begins. The reaction isstirred and cooled to 20. C. over a period of about two hours. Theproduct is then filtered, washed with 100 cc. cold Skellysolve C anddried in vacuum at 50 C. overnight. The crude dehydroabietylamineacetate is obtained as minute, colorless needles melting at 139.5-142.5C. Ultraviolet spectral analysis shows the crude material to contain82.8% of the theoretical amount of dehydrobietylamine, as compared with60.5 in the original Rosin Amine D. The crude product ts recrystallizedfrom Skellysolve C and yields a product melting at 144-145 C. Therecrystallized dehydrobietylamine acetate contains 87.8% of thetheoretical amount of dehydroabietylamine by spec tral analysis. Onchemical analysis the product is found to contain 76.49% C, 10.32% H,and 4.02% N, as compared with theoretical values of 76.48% C, 10.21% H,and 4.05% N.

Example II A solution of 6.0 gm. (0.1 mole) glacial acetic acid in 75cc. Skellysolve B is added dropwise over a period of about one-half hourto a stirred solution of 28.55 gm. (0.1 mole) Rosin Amine D in 350 cc.Skellysolve B at 25 C. The product crystallizes continuously during theaddition of the acetic acid. The reaction is allowed to stand forseveral hours to insure complete crystallization. The product is thenfiltered and washed with one 75 cc. and one 50 cc. portion ofSkellysolve B and is then dried at 50 C. in vacuum overnight. Thedehydroabietylamine acetate melts at 139.5-l42 C. Ultraviolet spectralanalysis shows the product to contain 86.3% of the theoretical amount ofdehydroabietylamine, as compared with 60.5% in the original Rosin AmineD.

Example III stirred at 15-20 C. for about one and one-half hourstocomplete crystallization. The product is filtered, washed with 20 cc.cold benzene and dried in vacuum at 50 C.

. 4 overnight. The dehydroabietylamine acetate melts at 137-140 C.Ultraviolet spectral analysis shows the product to contain 80.8% of thetheoretical amount of dehydroabietylamine, as compared with 60.5% in theoriginal Rosin Amine D.

Example IV Glacial acetic acid, 3.0 gm. (0.05 mole), is added to astirred solution of 14.27 gm. (0.05 mole) Rosin Amine D in 125 cc.methyl cyclohexane at 90 C. The solution is stirred, cooled and seeded,and at about 65 C., crystallization begins. Stirring and coolingcontinues for about three hours, after which the product is filtered,washed with 25 cc. cold methyl cyclohexane and dried. Thedehydroabietylamine acetate melts at l39-14l.5 C. Ultraviolet spectralanalysis shows the product to contain 83.8% of the theoretical amount ofdehydroabietylamine, as compared with 60.5% in the original Rosin AmineD.

Example V Glacial acetic acid, 3.0 gm. (0.05 mole), is added to astirred solution of 14.27 gm. (0.05 mole) Rosin Amine D in 100 cc.di-isopropyl ether at 60 C. The reaction immediately becomes nearlysolid with crystals. It is stirred and heated under reflux for about 15minutes, and then is stirred and cooled to 25 C. The product isfiltered, washed with 25 cc. di-isopropyl ether and dried in vacuum at50 C. overnight. The dehydroabietylamine acetate melts at 138.5-140.5 C.Ultraviolet spectral analysis shows the product to contain 80.4% of thetheoretical amount of dehydroabietylamine, as compared with 60.5% in theoriginal Rosin Amine D.

Example Vl Glacial acetic acid, 3.0 gm. (0.05 mole), is added to astirred solution of 14.27 gm. (0.05 mole) Rosin Amine D in 75 cc.chloroform at about 60 C. The reaction is stirred and cooled andcrystallization begins at about 50 C. The reaction is cooled for aboutan hour to a final temperature of about 20 C. The product is filtered,washed with 25 cc. cold chloroform, and dried in vacuum at 50 C.overnight. The dehydroabietylamine acetate melts at 133-138" C.Ultraviolet spectral analysis shows the product to contain 73.5% of thetheoretical amount of dehydroabietylamine, as compared with 60.5% in theoriginal Rosin Amine D.

Example VII Formic acid (98-100%), 2.3 gm. (0.05 mole), is added to asolution of 14.27 gm. (0.05 mole) Rosin Amine D in cc. Skellysolve C atabout 60 C. The clear solution is seeded with some previously preparedproduct and allowed to stand and crystallize overnight at roomtemperature. The solid is filtered, washed with two 50 cc. portions ofSkellysolve C and dried. The product, dehydroabietylamine formate, meltsat 141.5- 142.5 C. Recrystallization of the crude material fromSkellysolve C yields colorless needles melting at 147148 C. On chemicalanalysis the product is found to contain 76.11% C, 10.14% H, and 4.15%N, as compared with theoretical values of 76.08% C, 10.04% H, and 4.23%N. Ultraviolet spectral analysis shows the recrystallized product tocontain 83.9% of the theoretical amount of dehydroabietylamine, ascompared with 60.5%' in the original Rosin Amine D.

Example VIII material from Skellysolve yields minute, colorless :astaseaneedles melting at 137.5-139 C. On chemical analysis the product isfound to contain 76.79%1C, 10.30% H, and 4.00% N, as compared withtheoretical values of 76.82% C, 10.38% H, and 3.90% N. Ultravioletspectral analysis of the recrystallized product shows it to contain88.4% of the theoretical amount of 'dehydroabietylamine, as comparedwith 60.5% in the original Rosin Amine D. 1

Example IX n-Butyric acid, 4.40 gm. (0.05 mole), is added to a solutionof 14.27 gm. (0.05 mole) Rosin Amine D in 100 cc. Skellysolve C at 25 C.The solution is allowed to stand at 25 C. for about six hours tocomplete crystal; lization. The solid is filtered, washed with two 50cc. portions of Skellysolve C and dried. The product,dehydroabietylamine n-butyrate, melts at 126-130' C. Afterrecrystallization from Skellysolve C the-product is obtained as minute,colorless needles melting'at 132.5- 134 C. On chemical analysis theproduct is found to contain 77.10% C, 10.37% H, and 3.88% N, as comparedwith theoretical values of 77.16% C, 10.52% H, and 3.75% N. Ultravioletspectral analysis of the recrystallized product shows it to contain89.6% of the theoretical amount of dehydroabietylamine, as compared with60.5% in the original Rosin Amine D.

Example X n-Caproic acid, 5.81 gm. (0.05 mole), is added to a solutionof 14.27 gm. (0.05 mole) Rosin Amine D in 75 cc. Skellysolve C at 25 C.Crystallization is induced by scratching the walls of the flask. Thereaction mixture is allowed to stand at room temperature overnight. Thesolid is then filtered, washed with 40 cc. Skellysolve C and dried. Theproduct, dehydroabietylamine n-caproate, melts at 107.5109.5 C.Recrystallization of the crude material from Skellysolve C yieldsminute, colorless needles melting at 110-111 C. On chemical analysis theproduct is found to contain 77.70% C, 11.02% H, and 3.45% N, as comparedwith theoretical values of 77.75% C, 10.80% H, and 3.49% N. Ultravioletspectral analysis shows the recrystallized product to contain 90.1% ofthe theoretical amount of dehydroabietylamine, as compared with 60.5% inthe orignial Rosin Amine D.

While the Rosin Amine D used in the present examples has adehydroabietylamine content of about 60.5% theoretical, a similar markedincrease in the purity of the dehydroabietylamine is obtained when usingRosin Amine D in which the percentage of dehydroabietylamine variesbetween about 40% and 70%.

Others may readily adapt the invention for use under various conditionsof service, by employing one or more of the novel features disclosed orequivalents thereof. As at present advised with respect to the apparentscope of my invention, I desire to claim the following subject matter.

I claim:

1. A method of preparing relatively pure dehydroabietylamine compoundswhich comprises contacting the lower fatty acid salts of a mixture ofhydroabietylamines having a substantial proportion ofdehydroabietylamine and a lesser proportion of dihydroabietylamine andtetrahydroabietylamine with a non-polar organic solvent in which thesaid dehydroabietylamine fatty acid salt is relatively insoluble, saidsolvent being present in an amount of at least about 5 cc. per gram ofsaid mixture of hydroabietylamines, allowing the saiddehydroabietylamine fatty acid salt to crystallize in said solvent, andseparating the said crystalline fatty acid salt of dehydroabietylaminein a relatively pure form from the fatty acid salts ofdihydroabietylamine and tetrahydroabietylamine in said solvent.

2. A method of preparing relatively pure dehydroabietylamine compoundswhich comprises contacting the lower fatty acid salts of a mixture ofhydroabietylamines having a-substantial proportion ofdehydroabietylamine and a lesser proportion of dihydroabietylamine andtetra hydroabietylamine with a non-polar organic solvent, said solventbeing present in an amount of at least about 5 cc; per gram of saidmixture of hydroabietylamines, allow ing the said dehydroabietylaminefatty acid salt to crystal lize in said slovent, and separating the saidcrystalline fatty acid salt of dehydroabietylamine in a relatively pureform from the fatty acid salts of dihydroabietylamine andtetrahydroabietylamine in said solvent. 1

3. A method of preparing relatively pure dehydroabietylamine compoundswhich comprises contacting the lower fatty acid salts of a mixture ofhydroabietylaminesjhaving a substantial proportion ofdehydroabietylamine and a lesser proportion of dihydroabietylv amine andtetrahydroabietylamine with a non-polar organic solvent, said solventbeing present in an amount between about 5 to 15 cc. per gram of thesaid mixture of hydroabietylamines, allowing the saiddehydroabietylamine fatty acid salt to crystallize in said solvent, andseparating the said crystalline fatty acid salt of dehydroabietylaminein a relatively pure form from the fatty acid saltsofdihydroabietylamine and tetrahydroabietylamine in said solvent.

4. A method of preparing a relatively pure dehydroabietylamine compoundwhich comprises reacting a lower fatty acid with a hydroabietylaminemixture having a substantial proportion of dehydroabietylamine and alesser proportion of dihydroabietylamine and tetrahydroabietylamine in anon-polar organic solvent in which the dehydroabietylamine lower fattyacid salt is relatively insoluble, said solvent being present in anamount of at least about 5 cc. per gram of said mixture ofhydroabietylamines allowing the lower fatty acid salt of thedehydroabietylamine to crystallize in said organic solvent, andseparating the said crystalline fatty acid salt of dehydroabietylaminein a relatively pure form from the fatty acid salts ofdihydroabietylamine and tetrahydroabietylamine in said solvent.

5. A method of preparing a relatively pure dehydroabietylamine compoundwhich comprises reacting a lower fatty acid with a hydroabietylaminemixture having a substantial proportion of dehydroabietylamine and alesser proportion of dihydroabietylamine and tetrahydroabietylamine in anon-polar organic solvent, said solvent being present in an amount of atleast about 5 cc. per gram of said mixture of hydroabietylamines,allowing the lower fatty acid salt of the dehydroabietylamine, tocrystallize in said non-polar organic solvent, and separating the saidcrystalline lower fatty acid salt of dehydroabietylamine in relativelypure form from the fatty acid salts of dihydroabietylamine andtetrahydroabietylamine in said solvent.

6. A method of preparing a relatively pure dehydroabietylamine compoundwhich comprises reacting a lower fatty acid with a hydroabietylaminemixture having a substantial proportion of dehydroabietylamine and alesser proportion of dihydroabietylamine and tetrahydroabietylamine in anon-polar organic solvent, said solvent being present in an amountbetween about 5 to 15 cc. per gram of hydroabietylamine mixture,allowing the lower fatty acid salt of the dehydroabietylamine tocrystallize in said non-polar organic solvent, and separating the saidcrystalline lower fatty acid salt of dehydroabietylamine in relativelypure form from the fatty acid salts of dihydroabietylamine andtetrahydroabictylamine in said solvent.

7. A method of obtaining a relatively pure dehydroabietylamine compoundwhich comprises reacting a lower fatty acid with a hydroabietylaminemixture having therein a major proportion of dehydroabietylamine and aminor proportion of dihydroabietylamine and tetrahydroabietylamine in anon-polar organic solvent heated to at least about 60 C., said solventbeing present in an amount of at least about 5 cc. per gram of saidmixture of hydroabietylamines, allowing the lower fatty acid salt ofdehydroabiet'ylamine to crystallize in the said solvent, and separatingthe crystalline dehydroabietylamine lower fatty acid salt in arelatively pure form from the said solvent.

'8. A method of obtaining a relatively pure dehydroabietylamine compoundwhich comprises reacting acetic acid with hydroabietylamine mixturehaving a major proportion of dehydroabietylamine and a minor proportionof dihydroabietylamine and tetrahydroabietylamine in a pctroleumhydrocarbon solvent heated to at least about 60 C., said solvent beingpresent in an amount of at least about 5 cc. per gram of said mixture ofhydroabietylamines, allowing the acetic acid salt of dehydroabietylamineto crystallize in the said solution, and separating the crystallinedehydroabietylamine acetic acid salt in a relatively pure form from thesaid solvent.

9. A method of obtaining a relatively pure dehydroabietylamine compoundwhich comprises reacting a lower fatty acid with a hydroabietylaminemixture having a major proportion of dehydroabietylamine and a minorproportion of dihydroabietylamine and tetrahydroabietylamine in anon-polar organic solvent at about room temperature, said solvent beingpresent in an amount of at least about 5 cc. per gram of said mixture ofhydroabietylamines, said lower fatty acid being added to the saidhydroabietylamine mixture in small increments, allowing the lower fattyacid salt of dehydroabietylamine to crystallize in the said solvent, andseparating the crystalline salt of dehydroabietylamine lower fatty acidsalt from said solvent in a relatively pure form.

10. A method of obtaining a relatively pure dehyd to abietylaminecompound which comprises reacting acetic acid with a'hydroabietylaminemixture having a major proportion of dehydroabi'etylamine and a minorproportion of dihydroabietylamine and tetrahydroabietylamine in apetroleum hydrocarbon solvent at about room temperature, said solventbeing present in an amount of at least about 5 cc. per gram of saidmixture of hydroabietylamines, said acetic acid being added to the saidhydroabietylamine mixture in small increments, allowing the acetic acidsalt of dehydroabietylamine to crystallize in the said solvent,'andseparating the crystalline dehydroabietylamine acetic acid salt fromsaid solvent in relatively pure form.

References Cited in the file of this patent UNITED STATES PATENTS2,520,901 Benoit Sept. 5, 1950 2,532,101 Kai-man Nov. 28, 1950 FOREIGNPATENTS 640,402 Great Britain July 19, 1950 OTHER REFERENCES HighPolymers, vol. 'Myer-Interscience Publishers 1110., N. Y., N. Y., page576 (1942).

1. A METHOD OF PREPARING RELATIVELY PURE DEHYDROABIETYLAMINE COMPOUNDSWHICH COMPRISES CONTACTING THE LOWER FATTY ACID SALTS OF A MIXTURE OFHYDROABIETYLAMINES HAVING A SUBSTANTIAL PROPORTION OFDEHYDROABIETYLAMINEE AND A LESSER PROPORTION OF DIHYDROABIETYLAMINE ANDTETRAHYDROABIETYLAMINE WITH A NON-POLAR ORGANIC SOLVENT IN WHICH THESAID DEHYDROABIETYLAMINE FATTY ACID SALT IS RELATIVELY INSOLUBLE, SAIDSOLVENT BEING PRESENT IN AN AMOUNT OF AT LEAST ABOUT 5 CC. PER GRAM OFSAID MIXTURE OF HY-DROABIETYLAMINES, ALLOWING THE SAIDDEHYDROABIETYLAMINE FATTY ACID SALT TO CRYSTALLIZE IN SAID SOLVENT, ANDSEPARATING THE SAID CRYSTALLINE FATTY ACID SALT OF DEHYDROABIETYLAMINEIN A RELATIVELY PURE FORM FROM THE FATTY ACID SALTS OFDIHYDROABIETYLAMINE AND TETRAHYDROABIETYLAMINE IN SAID SOLVENT.